Processes for preparing 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile and for preparing sulindac

Abstract

The disclosure provides processes for preparing 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile and for preparing sulindac, relating to the field of medicine. The former comprises mixing 6-fluoro-2-methyl-1-indanone, cyanoacetic acid, a first organic solvent and an acetic acid-based catalyst to proceed with a first condensation reaction to give a first condensation reaction solution, which contains 5-fluoro-2-methyl-3-indanacetonitrile; and mixing the first condensation reaction solution, per se, with a base, a second organic solvent and 4-(methylthio)benzaldehyde to proceed with a second condensation reaction to give 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile. The process is a one-pot process without separation of 5-fluoro-2-methyl-3-indanacetonitrile from the solvent, shortening the synthetic route, simplifying the preparation process and improving the 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile yield.

The invention claimed is: 
     
       1. A process for preparing 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile, comprising:
 mixing 6-fluoro-2-methyl-1-indanone, cyanoacetic acid, a first organic solvent and an acetic acid-based catalyst to proceed with a first condensation reaction to give a first condensation reaction solution, which contains 5-fluoro-2-methyl-3-indanacetonitrile; and 
 mixing the first condensation reaction solution, per se, with a base, a second organic solvent and 4-(methylthio)benzaldehyde to proceed with a second condensation reaction to give 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile. 
 
     
     
       2. The process according to  claim 1 , wherein the first condensation reaction is carried out at 100 to 140° C. for 5 to 30 hours. 
     
     
       3. The process according to  claim 1 , wherein the second condensation reaction is carried out at 50 to 90° C. for 3 to 8 hours. 
     
     
       4. The process according to  claim 1 , wherein the base comprises one or more of: sodium hydroxide, sodium ethoxide, sodium methylate, potassium hydroxide, sodium hydride and potassium hydride. 
     
     
       5. The process according to  claim 1 , further comprising: after the second condensation reaction, subjecting a product of the second condensation reaction to cooling, pH adjustment, layer separation, evaporation of an organic layer and purification sequentially. 
     
     
       6. A process for preparing sulindac, comprising:
 preparing 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile according to  claim 1 , and 
 mixing 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile with a solvent and a photocatalyst to proceed with a photo-catalytic oxidation and hydrolysis reaction under light irradiation to give sulindac, 
 wherein, the photocatalyst is a metal chalcogenide nanomesh, the metal chalcogenide having a formula MX2, where M represents one or more of Mo, W and V, and X represents one or more of S, Se and Te. 
 
     
     
       7. A process for preparing sulindac, comprising:
 preparing 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile according to  claim 2 , and 
 mixing 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile with a solvent and a photocatalyst to proceed with a photo-catalytic oxidation and hydrolysis reaction under light irradiation to give sulindac, 
 wherein, the photocatalyst is a metal chalcogenide nanomesh, the metal chalcogenide having a formula MX2, where M represents one or more of Mo, W and V, and X represents one or more of S, Se and Te. 
 
     
     
       8. A process for preparing sulindac, comprising:
 preparing 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile according to  claim 3 , and 
 mixing 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile with a solvent and a photocatalyst to proceed with a photo-catalytic oxidation and hydrolysis reaction under light irradiation to give sulindac, 
 wherein, the photocatalyst is a metal chalcogenide nanomesh, the metal chalcogenide having a formula MX2, where M represents one or more of Mo, W and V, and X represents one or more of S, Se and Te. 
 
     
     
       9. A process for preparing sulindac, comprising:
 preparing 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile according to  claim 4 , and 
 mixing 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile with a solvent and a photocatalyst to proceed with a photo-catalytic oxidation and hydrolysis reaction under light irradiation to give sulindac, 
 wherein, the photocatalyst is a metal chalcogenide nanomesh, the metal chalcogenide having a formula MX2, where M represents one or more of Mo, W and V, and X represents one or more of S, Se and Te. 
 
     
     
       10. A process for preparing sulindac, comprising:
 preparing 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile according to  claim 5 , and 
 mixing 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile with a solvent and a photocatalyst to proceed with a photo-catalytic oxidation and hydrolysis reaction under light irradiation to give sulindac, 
 wherein, the photocatalyst is a metal chalcogenide nanomesh, the metal chalcogenide having a formula MX2, where M represents one or more of Mo, W and V, and X represents one or more of S, Se and Te. 
 
     
     
       11. The process according to  claim 6 , further comprising: after the photo-catalytic oxidation and hydrolysis reaction, subjecting a product of the reaction to a first filtration, distillation, a second filtration and purification sequentially. 
     
     
       12. The process according to  claim 7 , further comprising: after the photo-catalytic oxidation and hydrolysis reaction, subjecting a product of the reaction to a first filtration, distillation, a second filtration and purification sequentially. 
     
     
       13. The process according to  claim 8 , further comprising: after the photo-catalytic oxidation and hydrolysis reaction, subjecting a product of the reaction to a first filtration, distillation, a second filtration and purification sequentially. 
     
     
       14. The process according to  claim 9 , further comprising: after the photo-catalytic oxidation and hydrolysis reaction, subjecting a product of the reaction to a first filtration, distillation, a second filtration and purification sequentially. 
     
     
       15. The process according to  claim 10 , further comprising: after the photo-catalytic oxidation and hydrolysis reaction, subjecting a product of the reaction to a first filtration, distillation, a second filtration and purification sequentially. 
     
     
       16. The process according to  claim 6 , wherein the photo-catalytic oxidation and hydrolysis reaction is carried out at 20 to 80° C. for 2 to 12 hours. 
     
     
       17. The process according to  claim 7 , wherein the photo-catalytic oxidation and hydrolysis reaction is carried out at 20 to 80° C. for 2 to 12 hours. 
     
     
       18. The process according to  claim 8 , wherein the photo-catalytic oxidation and hydrolysis reaction is carried out at 20 to 80° C. for 2 to 12 hours. 
     
     
       19. The process according to  claim 6 , wherein a mass ratio of the photocatalyst to 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indanacetonitrile is from 0.5%: 1 to 3%: 1. 
     
     
       20. The process according to  claim 6 , wherein the solvent is an acetic acid solution with a mass ratio of acetic acid to water being from about 0.25:1 to 4:1.